Substituted benzamidopiperidinopropanes



2,798,072 Patented July 2 1957 temperature. They are relatively insoluble in water, but

2,793,072 are soluble in the common polar organic solvents. The

acid addition salts of those bases are in eneral water- SSTITUTED BENZAMIDOPIPERIDINO' soluble crystalline substances g PROPANES e 5 The new substituted benzamidoplperidinopropanes and Albert llohland, Indianapolis, Ind., assignor to Eli Lilly their salts are local anesthetics characterized by stability, and Company, Indianapolis, Ind., a corporation of Inlack of irritation and long duration of action. For diana I therapeutic use, the compounds can be advantageously No Drawing. Original application December 9 1953, utilized as water solutions of the ac d addition salts, or

Serial No. 397,261' Divided and this application 00 10 the salts or bases can be incorporated into various pharmatober 24, 19559591; 542,502 ceutical extending media such as ointments, solutions,

jellies, oils, lotions, suspending media and the like. 2 a m (CL 260-494) The new compounds can be prepared by methods known to the art, exemplified by the following series of equations, Th1s invention relates to substituted benzamidopropylin which R and R1 have the same significance as hereamines and more particularly to substituted l-benzamidoinabove.

orn-om CH -CH1 HONH: O=C CH CHZ CH3 HON=(|}CHCH2N CH2 R1 GHQ-C R1 CHz-C:

CHz- -CHg NHzCH-CH-CHz-N /CH2 1 CHz-CH,

I COOL i i CHg-CH, RooNH-on-o11ornN on ill CHz-Ofia 3-piperidinopropanes and their acid addition salts, and to the preparation thereof.

The bases of the substituted benzamidopiperidinopropanes of the present invention may be represented by the formula Referring to the equations, it will be seen that a substituted piperidinopropiophenone is treated with hydroxylamine to produce the corresponding oxime, which is hydrogenated to form a substituted phenylpiperidinopropylamine. The piperidinopropylamine is reacted with a substituted benzoyl chloride to form the correspondingly substituted benzamidopiperidinopropane.

Aswi ll be evident, the compounds contain a basic nitrogen atom, which can react with acids to form acid addition salts. Such salts are readily prepared by the usual methods of the art, e. g., the reaction of stoichiometrically equivalent amounts of the desired base and a selected acid in a mutual inert solvent. Examples of acids which are suitable for the preparation of acid addition salts of the invention are inorganic acids, for example, hydrochloric, nitric, sulfuric, phosphoric, and the like acids; and organic acids, for example, benzoic, acetic, salicyclic, propionic, maleic, citric and the like acids. The preferred salts are the pharmaceutically useful salts i. e., acid addition salts which are not materially more 3. toxic or irritating than the bases from which they are prepared, and which possess physical characteristics that render them suitable for incorporation into the desired pharmaceutical preparations.

This application is a division of my co-pendingapplication Serial No. 397,261,. filed December 9, 1953, which was a continuation-in-part of my co-pending application. Serial'No. 319,783, filed November l0,v 1952, now abancloned;

The following examples more specifically illustrate the preparation and properties of the compounds of this invention.

EXAMPLE 1' Preparation of J-benzamido-Lphenyl 3 piperidino propane hydrochloride A. mixture. of. 101.5 g. of fl-piperidinopropiophenone' hydrochloride, prepared by the method of Adams, Or?

Analysis.-Calculated for C14H21N2OC1: N, 10.40 (:1;

13.19. Found: N, 10.00; Cl, 13.13.

A mixture of 10 g. of Raney nickel caltalyst, 81.5 giofi.

p-piperidinopropiophenone oxime, 200 ml. of ethanol and 75 ml. of liquid ammonia was placed in an antoclave, and reduced under 1400 lbs. pressure of hydrogen for one hour at 70 to 110 C. The reaction mixture was filtered and fractionally distilled under reduced pressure and. the 1-phenyl-3-piperidinopropylamine formed in the reaction distilled at 133134 C. at a pressure of 1 mm. of mercury. The index of refraction at 25 C. was 1.5231.

Analysis.--Calculated for C14H22N2: N,.12.83. Found: N, 12.32.

The maleate salt of 1-phenyl-3-piperidinopropylamine meltedat about ISO-151 C.

Analysis.Calculated for C22H30N2O3: C, 58.65; H, 6.71; N, 6.22. Found: C, 5.8.88; H, 6.78; N, 6.48.

A mixture of 24 g. of 1 phenyl-I'rpiperidinopropylamine, 24 ml. of benzoyl chloride, 300 ml. of benzene and ml. of dry pyridine was allowed to stand at room temperature for about sixteen hours. A suflicient amount of ethyl ether was thereafter added to bring about complete precipitation of the l-benzamido-1-phenyl-3-piperidinopropane hydrochloride formed in the reaction. The

precipitate was removed by filtration and recrystallizedv Analysis.-Calculated for C21H2 1N2OC1': N, 7.81; CI,

9.88. Found: N, 7.90;. 01 9.92. EXAMPLE 2 Preparation of 1-benzamido-1-phenyl-3-piperidinopropane Fifty g. of crystalline l-benzamido-1-phenyl-3 piperidinopropane hydrochloride were shaken with a mixture of 200 ml. of ether and 200 ml. of dilute aqueous am moni'um hydroxide. The ether layer containing the free base was dried over anhydrous magnesium sulfate and the ether was removed by distillation. The residue was 4. dissolved in about ml. of hot ethyl acetate and petroleum ether was added until crystallization occurred. The crystalline precipitate of 1-benzamido-1-phenyl-3- piperidinopropane after recrystallization from a mixture of ethyl acetate and petroleum ether melted at about ll1-112 C.

Analysis;Calculated' for C21H26N2OZ N, 8.09. Found: N, 8.25.

EXAMPLE 3 Preparation of l-benzamido-Z-methyl-1-phenyl-3-piperidinopropane hydrochloride a-Methyl-fi-piperidinopropiophenone prepared according to the method of Ruddy, I; A. C. S. 72, 718 (1950), was condensed with hydroxylamine to form a-methyl-fipiperidinopropiophenone oxime. The oxime was reduced-with Raney nickel according to the procedure of Example. 1 to form. l-phenyl-2-methyl-3-piperidinopropyl amine.

l-phenyl-2-methyl-3-piperidinopropylamine thus prepared boiled at about 128129 C. at a pressure of 0.5 mm. of mercury. The index of refraction at 25 C. was 1.5250.

Anolysis.Calculated=for C15H24N2: N, 12.06. Found: N, 12.18.

A mixturev of 9.7 g. of 1-phenyl-2-methyl-3-piperidinopropylamine, 9.7 ml. of benzoyl chloride, 20 ml. of dry pyridine and 100 ml. of benzene was allowed to stand for about sixteen hours at room temperature. A sufiicient amount of ethyl ether was added to the reaction mixture to bring about a complete precipitation of the l-benzamido-l-phenyl-2-methyl-3-piperidinopropane hydrochloride formed in the reaction. The precipitate was separated-,. and after recrystallization from a mixture of ethyl acetate and methanol, the l-benzamido-l-phenyl-Z- methyl-3-piperidinopropane hydrochloride melted at about 262263 C., with decomposition.

Analysis.Calcu1ated for C22H29N2OC1: N, 7.51; CI, 9.51. Found? N, 7.46; Cl, 9.40.

1-benzamido-1-phenyl-2 methyl 3-piperidinopropane was prepared from l-benzamido-l-phenyl-2-methyl-3- piperidinopropane hydrochloride by the procedure of Example 2.

EXAMPLE 4 Preparation of 1-(4'-cyclohexyloxybenzamido)-1-phenyl- 3-piperidinopropane hydrochloride 1-phenyl-3-piperidinopropylamine was prepared according to the process of Example 1. A mixture of 5.8 g. of 4-cyclohexyloxybenzoyl chloride, 8 ml. of pyridine, 4 g. of 1-phenyl-3-piperidinopropylamine and 50 ml. of benzene was warmed on a steam bath for about one hour. The reaction mixture was cooled, and suflicient ether was added to bring about complete precipitation of the 1- 4'-cyclohexyloxybenzamido) -1.-phenyl-3 -piperidinopropa-ne. hydrochloride formed in the'reaction. The precipitate wasremoved and recrystallized from a mixture of i'sopropanol' and ether and then from'a mixture of methanol and ethyl acetate. The l-(4'-cyclohexyloxybenzamido)-1-phenyl-3 piperidinopropane hydrochloride thus prepared melted at about 18'3-184 C.

Analysis.-Calculated for C2'1H3sN2O2'HCl: N, 6.13; Cl, 7.76. Found: N, 6.28; CI, 7.66.

By subjecting 1-(4'-cyclohexyl0xybenzamido)-1-phenyl-3-piperidinopropane hydrochloride to the procedure of Example 2, there was obtained 1-(4'-cyclohexyloxybenzamido) -1-phenyl-3-piperidinopropane.

EXAMPLE 5 Preparation of 1-( 4'-cycl0hexyloxybenzamido) -1-phenyl- Z-mierhyl-3 piperidinopropane hydrochloride A reaction mixture containing 10 g. of 1-phenyl-2- methyl-3'-piperidinopropylarnine prepared according to the procedure of Example 3, 13.8 g. of p-cyclohexyloxybenzoyl chloride, 20 ml. of dry pyridine and 100 ml. of benzene was refluxed on a steam bath for about one hour. The reaction mixture was diluted with about 150 ml. of ethyl acetate, and cooled, whereupon 1-(4-cyclohexyloxybenzamido)-l-phenyl-2-methyl 3 piperidinopropane hydrochloride precipitated. The precipitate was removed by filtration and was crystallized from ethyl acetate, whereupon l- (4-cyclohexyloxybenzamido) -1-phenyl-2- methyl-3-piperidinopropane hydrochloride was obtained, melting at about 220221 C. with decomposition.

Analysis.Calculated for CzsHsaNzOz-HCI: Cl, 7.53. Found: Cl, 7.31.

1-(4'-cyclohexyloxybenzamido)-l-phenyl Z-methyl 3- piperidinopropane base was prepared from 1-(4'-cyclohexyloxybenzamido)-l-phenyl-2-methyl-3 piperidinopropane hydrochloride by the procedure of Example 2.

6 piperidinopropane (prepared according to the procedure of Example 2) in 100 ml. of ethanol is added a solution of 3.8 g. of maleic acid in 10 ml. of ethanol. The solution is thoroughly mixed, and evaporated to dryness in vacuo, whereby the maleic acid salt of l-benzamidol-phenyl-3-piperidinopropane is recovered.

By following the above-described procedure, except that sulfuric acid, citric acid, phosphoric acid, lauric acid, acetic acid and butyric acid are used, the sulfate, citrate, phosphate, laurate, acetate and butyrate salts of l-benzamido-1-phenyl-3-piperidinopropane, respectively, are recovered.

I claim:

1. A compound selected from the group consisting of 1-(4-cyclohexyloxybenzamido)-l-phenyl 3 piperidinopropane represented by the formula:

CHz-CH: I /CH5CH2 o o-o-o ONHCHCHzCHzN\ on, CH2-O 2 GHzCa EXAMPLE 6 and acid addition salts thereof. Preparation of I-benzamido-I-phenyl-3-piperidinopropane 2 1-(4' cyclohexyl()Xybenzamido)-1..phenyl-3-piperidimaleate To a solution of 32.2 g. of 1-benzamido-1-phenyl-3- CH -CH nopropane represented by the formula:

CHTCHR CH: CHPCEQ No references cited. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1-(4''-CYCLOHEXYLOXYBENZAMIDO)-1-PHENYL -3- PIPERIDINOPROPANE REPRESENTED BY THE FORMULA: 